title: Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma.
abstract: T-oligo, an 11-base oligonucleotide homologous to the 3'-telomeric overhang, is a novel, potent therapeutic modality in melanoma and multiple other tumor types. T-oligo is proposed to function in a manner similar to experimental disruption of the telomere overhang and induces DNA damage responses including apoptosis, differentiation and senescence. However, important components involved in T-oligo induced responses are not defined, particularly the role of p53, TRF1 and TRF2 in mediating the T-oligo induced responses. In MU, PM-WK, and MM-MC melanoma cells, exposure to T-oligo upregulates p53 expression and phosphorylation, resulting in cellular differentiation and activation of a caspase-mediated apoptotic cascade. However, siRNA-mediated knockdown of p53 completely blocks T-oligo induced differentiation and significantly decreases apoptosis, suggesting that p53 is an important mediator of T-oligo induced responses. In addition, we characterized the roles of telomere binding proteins, TRF1, TRF2, and tankyrase-1, in T-oligo induced damage responses. We demonstrate that tankyrase-1 activity is required for initiation of T-oligo induced damage responses including p53 phosphorylation and reduction of cellular proliferation. These results highlight TRF1, TRF2, tankyrase-1 and p53 as important elements in T-oligo mediated responses and suggest new avenues for research into T-oligo's mechanism of action.
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, Illinois, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Pitman
authors.forename: Luke
authors.initials: L
authors.lastname: Wojdyla
authors.forename: Neelu
authors.initials: N
authors.lastname: Puri
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016615:Telomere / Q000235:genetics; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D038501:Tankyrases; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; C544261:XAV939; C418109:TNKS protein, human